1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles containing arylsulfones at the 9-position

ABSTRACT

The present invention are substituted 9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles (X) and unsubstituted 9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles (XI) such as the compound of EXAMPLE 13  
                 
 
     which are useful in treating depression, obesity and other CNS disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the following provisionalapplication: U.S. Ser. No. 60/144574, filed Jul. 19, 1999, under 35 USC119(e)(i).

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention is substituted9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles (X) which areuseful for treating anxiety, depression and other CNS disorders inhumans and animals.

[0004] 2. Description of the Related Art

[0005] U.S. Pat. No. 3,652,588 discloses6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles which were useful fortranquilizing and sedating mammals to suppress hunger in mammals. Thisdocument discloses that there can be substitution at the 9-position.However, those substituents are limited to hydrogen, alkyl, alkoxy andhalogen.

[0006] U.S. Pat. No. 3,839,357 discloses6-benzyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles which were usefulfor tranquilizing mammals. This document discloses that there can besubstitution at the 9-position. However, those substituents are limitedto hydrogen, alkyl, alkoxy and halogen.

[0007] U.S. Pat. No. 3,676,558 discloses6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles which were useful tosuppress hunger in mammals. This document discloses that there can besubstitution at the 9-position. However, it is limited to hydrogen,alkyl, alkoxy and halogen.

SUMMARY OF INVENTION

[0008] Disclosed is a 9-arylsulfone of the formula (XII)

[0009] where R₃ is:

[0010] (1) —H,

[0011] (2) C₁-C₄ alkyl,

[0012] (3) C₀-C₄-φ where the -φ substituent is optionally substitutedwith 1 or 2

[0013] (a) —F, —Cl, —Br, —I,

[0014] (b) —O—R₃₋₁ where R₃₋₁ is:

[0015] —H,

[0016] C₁-C₄ alkyl,

[0017] -φ,

[0018] (c) —CF₃,

[0019] (d) —CO—NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃ are —H and C₁-C₄ alkyl, andwhere R₃₋₂ and R₃₋₃ are taken with the attached nitrogen atom to form aring selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyland 1-morpholinyl,

[0020] (e) —NH—SO₂—R₃₋₄ where R₃₋₄ is —H and C₁-C₄ alkyl,

[0021] (f) —NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃ are as defined above,

[0022] (g) —NR₃₋₄—CO—R₃₋₄ where R₃₋₄ is as defined above,

[0023] (h) —SO₂—NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃ are as defined above,

[0024] (I) —C≡N,

[0025] (j) —NO₂,

[0026] where R_(N) is:

[0027] (1) —H,

[0028] (2) C₁-C₄ alkyl,

[0029] (3) C₀-C₄-φ where the -φ substituent is optionally substitutedwith 1 or 2

[0030] (a) —F, —Cl, —Br, —I,

[0031] (b) —O—R_(N-1) where R_(N-1) is

[0032] —H,

[0033] C₁-C₄ alkyl,

[0034] -φ,

[0035] (c) —CF₃,

[0036] (d) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are —H andC₁-C₄ alkyl, and where R₃₋₂ and R₃₋₃ are taken with the attachednitrogen atom to form a ring selected from the group consisting of1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl,

[0037] (e) —NH—SO₂—R_(N-4) where R_(N-4) is —H and C₁-C₄ alkyl,

[0038] (f) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedabove,

[0039] (g) —NR_(N-4)—CO—R_(N-4) where R_(N-4) is as defined above,

[0040] (h) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as definedabove,

[0041] (I) —C≡N,

[0042] (j) —NO₂,

[0043] where R_(X) is:

[0044] (1) —H

[0045] (2) —F, —Cl, —Br, —I,

[0046] (3) —O—R_(X-1) where R_(X-1) is:

[0047] —H,

[0048] C₁-C₄ alkyl,

[0049] -φ,

[0050] (4) —CF₃,

[0051] (5) —CO—NR_(X-2)R_(X-3) where R_(X-2) and R_(X-3) are as definedabove,

[0052] (6) —NH—SO₂—R_(X-4) where R_(X-4) is as defined above,

[0053] (7) —NR_(X-2)R_(X-3) where R_(X-2) and R_(X-3) are as definedabove,

[0054] (8) —NR_(X-4)—CO—R_(X-4) where R_(X-4) is as defined above,

[0055] (9) —SO₂—NR_(X-2)R_(X-3) where R_(X-2) and R_(X-3) are as definedabove,

[0056] (10) —C≡N,

[0057] (11) —NO₂;

[0058] where R₉ is:

[0059] (1) —H,

[0060] (2) —F, —Cl,

[0061] (3) C₁-C₄ alkyl,

[0062] (4) C₁-C₃ alkoxy,

[0063] (5) —CF₃,

[0064] (6) C₀-C₄-φ where the -φ substituent is optionally substitutedwith 1 or 2

[0065] (a) —F, —Cl, —Br, —I,

[0066] (b) —O—R₉₋₁ where R₉₋₁ is:

[0067] —H,

[0068] C₁-C₄ alkyl,

[0069] -φ,

[0070] (c) —CF₃,

[0071] (d) —CO—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are —H and C₁-C₄ alkyl, andwhere R₉₋₂ and R₉₋₃ are taken with the attached nitrogen atom to form aring selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyland 1-morpholinyl,

[0072] (e) —NH—SO₂—R₉₋₄ where R₉₋₄ is —H and C₁-C₄ alkyl,

[0073] (f) —NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above,

[0074] (g) —NR₉₋₄—CO—R₉₋₄ where R₉₋₄ is as defined above,

[0075] (h) —SO₂—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above,

[0076] (I) —C≡N,

[0077] (j) —NO₂

[0078] (7) —OR₉₋₁ where R₉₋₁ is as defined above,

[0079] (8) —CO—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above,

[0080] (9) —NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above,

[0081] (10) —NH—SO₂—R₉₋₄ where R₉₋₄ is as defined above,

[0082] (11) —NH—CO₂—R₉₋₂ where R₉₋₂ is as defined above, andpharmaceutically acceptable salts thereof.

[0083] Also disclosed are compounds which are intermediates in theproduction of the 9-arylsulfones (XII), the thio ethers of formula(III), the amines of formula (IV), the hydrazines of formula (V), thecompounds of formula (VII) and the protected 9-arylsulfones of formula(VIII) where PG is selected from the group consisting of φ—CH₂—, φ—CO—,φ—CH₂—CO₂— and —CO—O—C(CH₃)₃ and where R₉ and R_(X) are as definedabove.

[0084] Further disclosed is a method of treating a human who has acondition selected from the group consisting of anxiety, depression,schizophrenia, stress related disease, panic, a phobia, obsessivecompulsive disorder, obeisity, post-traumatic stress syndrome who is inneed of such treatment which comprises administering an effective amountof a 9-arylsulfone of the formula (XII).

DETAILED DESCRIPTION OF THE INVENTION

[0085] The unsubstituted 9-arylsulfones (IX) and substituted9-arylsulfones (X) are both prepared by means known to those skilled inthe art. The term 9-arylsulfones (XI) includes both the unsubstituted9-arylsulfones (IX), where R₃ is —H and substituted 9-arylsulfones (X)where R₃ is ≠ to —H. The process of preparation can be viewed as beingin two parts. The first part is the production of the appropriatelysubstituted hydrazone (V), see CHART A. The second part is the couplingand reaction of the appropriately substituted hydrazone (V) with the1-protected hexahydro-4H-azepine-4-one (VI) to give the intermediate(VII) and its transformation to the unsubstituted 9-arylsulfone (IX),see CHART B.

[0086] The appropriately substituted thiols (I) are either known tothose skilled in the art or can be readily prepared from known startingmaterials by means well known to those skilled in the art. There can beeither one or two R₉ substituents and R₉ includes —H, —F, —Cl, C₁-C₃alkyl, C₁-C₃ alkoxy and —CF₃; it is preferred that R₉ is —H, —F, —Cl, C₁alkyl, C₁ alkoxy, and —CF₃ and when F— it is preferred that it be in the4- or p-position. It is preferred that the R₉ substituent be in eitherthe 3- or 4-position.

[0087] The appropriately substituted thiol (I) is coupled with theappropriately substituted 4-chloro-1-nitrobenzene (II) by known means toproduce the thioether (III). There can be either one or two R_(X)groups. If R_(X) is other than —H, it should be part of the4-chloro-1-nitrobenzene (II) so that it will become part of the finalunsubstituted 9-arylsulfone (IX) when it is formed. It is most difficultto add the R_(X) substitutent (other than —H) to the unsubstituted9-arylsulfone (IX) once it is formed. Therefore, the R_(X) group shouldbe part of the appropriately substituted 4-chloro-1-nitrobenzene (II)when it is reacted with the thiol (I). R_(X) includes of —H, —F and —Cl;it is preferred that R_(X) is —H. The thioether (III) is then oxidizedwith hydrogen peroxide (30%) followed by reduction with rhodium oncarbon (5%), all of which is known to those skilled in the art, toproduce the amine (IV). The amine (IV) is then diazotized by (sodium)nitrite and (hydrochloric) acid followed by reduction with tinchloride/water to give the corresponding hydrazine (V).

[0088] The second part of the reaction, is well known to those skilledin the art, see U.S. Pat. Nos. 3,652,588, 3,676,558 and 3,839,357. Theonly difference between the process in those patents and that here isthe arylsulfone substituent at the 9-position. That substituent isalready in place in the hydrazine (V) prior to the reaction of the9-arylsulfone hydrazine (V) with the 1-protectedhexahydro-4H-azepine-4-one (VI) to produce the correspondinglysubstituted intermediate (VII). Suitable protecting groups (PG) includeφ—CH₂—, φ—CO—, φ—CH₂—CO₂— and —CO—O—C(CH₃)₃; it is preferred that theprotecting group be φ—CH₂— or φ—CO—. The cyclization of the intermediate(VII) to the corresponding protected arylsulfone (VIII) and then thedeprotection to the unsubstituted 9-arylsulfone (IX) all follow knownmethods. The protecting groups (PG) are readily removed by means wellknown to those skilled in the art. The unsubstituted 9-arylsulfone (IX)can then be substituted at the C3-position (R₃, ring nitrogen atom) aswell as on the indole nitrogen (R_(N)) as is known to those skilled inthe art. Alternatively, arylsulfone (VIII) can be alkylated with thedesired R_(N)—X substituent to give the protected indole (XI) which thenis deprotected to give the desired substituted 9-arylsulfone (X). UsefulR₃ groups include of —H and C₁-C₂ alkyl; it is preferred that R₃ be —H.Useful R_(N) groups include of —H and C₁-C₄ alkyl; it is preferred thatR_(N) is —H, C₁ alkyl and C₂ alkyl. The invention here is not theprocess chemistry but rather the novel products produced.

[0089] The preferred protecting group for the intermediates (VI), (VII)and (VIII) are benzyl and benzamide though other groups are operable asis known to those skilled in the art.

[0090] The 9-arylsulfones (XI) are amines, and as such form acidaddition salts when reacted with acids of sufficient strength.Pharmaceutically acceptable salts include salts of both inorganic andorganic acids. The pharmaceutically acceptable salts are preferred overthe corresponding free amines since they produce compounds which aremore water soluble and more crystalline. The preferred pharmaceuticallyacceptable salts include salts of the following acids methanesulfonic,hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic,citric, tartaric, fumaric, maleic, CH₃—(CH₂)_(n)—COOH where n is 0 thru4, HOOC—(CH₂)_(N)—COOH where n is as defined above. aa

[0091] The 9-arylsulfones (XI) of the present invention are useful totreat anxiety, depression, schizophrenia, stress related disease, panic,a phobia, obsessive compulsive disorder, obeisity, post-traumatic stresssyndrome and other CNS disorders. It is preferred that the 9-arylsulfones (XI) be used to treat anxiety for depression. To treat thesediseases the 9-arylsulfones (XI) are administered orally, sublingually,transdermally or parenterally to provide a dosage of about 0.1 to about50 mg/kg/day. It is preferred that the dosage range be from about 0.1 toabout 10 mg/kg/day. The 9-arylsulfones (XI) can be administered individed doses either two, three or four times daily. It is preferredthat the 9-arylsulfones (XI) be administered orally.

[0092] The exact dosage and frequency of administration depends on theparticular 9-arylsulfone(s) used, the particular disease being treated,the severity of the disease being treated, the age, weight, generalphysical condition of the particular patient, other medication theindividual may be taking as is well known to those skilled in the artand can be more accurately determined by measuring the blood level orconcentration of the 9-arylsulfone (XI) in the patient's blood and/orthe patient's response to the particular condition being treated.

Definitions and Conventions

[0093] The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

[0094] I. Conventions for Formulas and Definitions of Variables

[0095] The chemical formulas representing various compounds or molecularfragments in the specification and claims may contain variablesubstituents in addition to expressly defined structural features. Thesevariable substituents are identified by a letter or a letter followed bya numerical subscript, for example, “Z₁” or “R_(i)” where “i” is aninteger. These variable substituents are either monovalent or bivalent,that is, they represent a group attached to the formula by one or twochemical bonds. For example, a group Z₁ would represent a bivalentvariable if attached to the formula CH₃—C(═Z₁)H. Groups R_(i) and R_(j)would represent monovalent variable substituents if attached to theformula CH₃—CH₂— —C(R_(i))(R_(j))—H. When chemical formulas are drawn ina linear fashion, such as those above, variable substituents containedin parentheses are bonded to the atom immediately to the left of thevariable substituent enclosed in parenthesis. When two or moreconsecutive variable substituents are enclosed in parentheses, each ofthe consecutive variable substituents is bonded to the immediatelypreceding atom to the left which is not enclosed in parentheses. Thus,in the formula above, both R_(i) and R_(j) are bonded to the precedingcarbon atom. Also, for any molecule with an established system of carbonatom numbering, such as steroids, these carbon atoms are designated asC_(i), where “i” is the integer corresponding to the carbon atom number.For example, C₆ represents the 6 position or carbon atom number in thesteroid nucleus as traditionally designated by those skilled in the artof steroid chemistry. Likewise the term “R₆” represents a variablesubstituent (either monovalent or bivalent) at the C₆ position.

[0096] Chemical formulas or portions thereof drawn in a linear fashionrepresent atoms in a linear chain. The symbol “—” in general representsa bond between two atoms in the chain. Thus CH₃—O—CH₂—CH(R_(i))—CH₃represents a 2-substituted-1-methoxypropane compound. In a similarfashion, the symbol “═” represents a double bond, e.g.,CH₂═C(R_(i))—O—CH₃, and the symbol “°” represents a triple bond, e.g.,HC°C—CH(R_(i))—CH₂—CH₃. Carbonyl groups are represented in either one oftwo ways: —CO— or —C(═O)—, with the former being preferred forsimplicity.

[0097] Chemical formulas of cyclic (ring) compounds or molecularfragments can be represented in a linear fashion. Thus, the compound4-chloro-2-methylpyridine can be represented in linear fashion byN*═C(CH₃)—CH═CCl—CH═C*H with the convention that the atoms marked withan asterisk (*) are bonded to each other resulting in the formation of aring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinylcan be represented by —N*—(CH₂)₂—N(C₂H₅)—CH₂—C*H₂.

[0098] A rigid cyclic (ring) structure for any compounds herein definesan orientation with respect to the plane of the ring for substituentsattached to each carbon atom of the rigid cyclic compound. For saturatedcompounds which have two substituents attached to a carbon atom which ispart of a cyclic system, —C(X₁)(X₂)— the two substituents may be ineither an axial or equatorial position relative to the ring and maychange between axial/equatorial. However, the position of the twosubstituents relative to the ring and each other remains fixed. Whileeither substituent at times may lie in the plane of the ring(equatorial) rather than above or below the plane (axial), onesubstituent is always above the other. In chemical structural formulasdepicting such compounds, a substituent (X₁) which is “below” anothersubstituent (X₂) will be identified as being in the alpha (α)configuration and is identified by a broken, dashed or dotted lineattachment to the carbon atom, i.e., by the symbol “ - - - ” or “ . . .”. The corresponding substituent attached “above” (X₂) the other (X₁) isidentified as being in the beta (β) configuration and is indicated by anunbroken or solid line attachment to the carbon atom.

[0099] When a variable substituent is bivalent, the valences may betaken together or separately or both in the definition of the variable.For example, a variable R_(i) attached to a carbon atom as —C(═R_(i))—might be bivalent and be defined as oxo or keto (thus forming a carbonylgroup (—CO—) or as two separately attached monovalent variablesubstituents a-R_(i−j) and β-R_(i−k). When a bivalent variable, R_(i),is defined to consist of two monovalent variable substituents, theconvention used to define the bivalent variable is of the form“a-R_(i−j):β-R_(i−k)” or some variant thereof. In such a case botha-R_(i−j) and β-R_(i−k) are attached to the carbon atom to give—C(a-R_(i−j))(β-R_(i−k))—. For example, when the bivalent variable R₆,—C(═R₆)—is defined to consist of two monovalent variable substituents,the two monovalent variable substituents are a-R₆₋₁:β-R₆₋₂, . . .a-R₆₋₉:β-R₆₋₁₀, etc, giving —C(a-R₆₋₁)(β-R₆₋₂)—, . . .—C(a-R₆₋₉)(β-R₆₋₁₀)—, etc. Likewise, for the bivalent variable R₁₁,—C(═R₁₁)—, two monovalent variable substituents are a-R₁₁₋₁:β-R₁₁₋₂. Fora ring substituent for which separate a and β orientations do not exist(e.g. due to the presence of a carbon carbon double bond in the ring),and for a substituent bonded to a carbon atom which is not part of aring the above convention is still used, but the a and β designationsare omitted.

[0100] Just as a bivalent variable may be defined as two separatemonovalent variable substituents, two separate monovalent variablesubstituents may be defined to be taken together to form a bivalentvariable. For example, in the formula —C₁(R_(i))H—C₂(R_(j))H—(C₁ and C₂define arbitrarily a first and second carbon atom, respectively) R_(i)and R_(j) may be defined to be taken together to form (1) a second bondbetween C₁ and C₂ or (2) a bivalent group such as oxa (—O—) and theformula thereby describes an epoxide. When R_(i) and R_(j) are takentogether to form a more complex entity, such as the group —X—Y—, thenthe orientation of the entity is such that C₁ in the above formula isbonded to X and C₂ is bonded to Y. Thus, by convention the designation “. . . R_(i) and R_(j) are taken together to form —CH₂—CH₂—O—CO— . . . ”means a lactone in which the carbonyl is bonded to C₂. However, whendesignated “ . . . R_(j) and R_(i) are taken together to form—CO—O—CH₂—CH₂— the convention means a lactone in which the carbonyl isbonded to C₁.

[0101] The carbon atom content of variable substituents is indicated inone of two ways. The first method uses a prefix to the entire name ofthe variable such as “C₁-C₄”, where both “1” and “4” are integersrepresenting the minimum and maximum number of carbon atoms in thevariable. The prefix is separated from the variable by a space. Forexample, “C₁-C₄ alkyl” represents alkyl of 1 through 4 carbon atoms,(including isomeric forms thereof unless an express indication to thecontrary is given). Whenever this single prefix is given, the prefixindicates the entire carbon atom content of the variable being defined.Thus C₂-C₄ alkoxycarbonyl describes a group CH₃—(CH₂)_(n)—O—CO— where nis zero, one or two. By the second method the carbon atom content ofonly each portion of the definition is indicated separately by enclosingthe “C_(i)-C_(j)” designation in parentheses and placing it immediately(no intervening space) before the portion of the definition beingdefined. By this optional convention (C₁-C₃)alkoxycarbonyl has the samemeaning as C₂-C₄ alkoxy-carbonyl because the “C₁-C₃” refers only to thecarbon atom content of the alkoxy group. Similarly while both C₂-C₆alkoxyalkyl and (C₁-C₃)alkoxy(C₁-C₃)alkyl define alkoxyalkyl groupscontaining from 2 to 6 carbon atoms, the two definitions differ sincethe former definition allows either the alkoxy or alkyl portion alone tocontain 4 or 5 carbon atoms while the latter definition limits either ofthese groups to 3 carbon atoms.

[0102] When the claims contain a fairly complex (cyclic) substituent, atthe end of the phrase naming/designating that particular substituentwill be a notation in (parentheses) which will correspond to the samename/designation in one of the CHARTS which will also set forth thechemical structural formula of that particular substituent.

II. Definitions

[0103] All temperatures are in degrees Centigrade.

[0104] HPLC refers to high pressure liquid chromatography.

[0105] DMSO refers to dimethylsulfoxide.

[0106] DMF refers to dimethylfornamide.

[0107] Saline refers to an aqueous saturated sodium chloride solution.

[0108] Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

[0109] IR refers to infrared spectroscopy.

[0110] NMR refers to nuclear (proton) magnetic resonance spectroscopy,chemical shifts are reported in ppm (d) downfield fromtetramethylsilane.

[0111] -φ refers to phenyl (C₆H₅).

[0112] MS refers to mass spectrometry expressed as m/e, m/z ormass/charge unit. [M+H]⁺ refers to the positive ion of a parent plus ahydrogen atom. CI refers to electron impact. CI refers to chemicalionization. FAB refers to fast atom bombardment.

[0113] HRMS refers to high resolution mass spectrometry.

[0114] Pharmaceutically acceptable refers to those properties and/orsubstances which are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

[0115] When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

[0116] When the solubility of a solid in a solvent is used the ratio ofthe solid to the solvent is weight/volume (wt/v).

EXAMPLES

[0117] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, practice the presentinvention to its fullest extent. The following detailed examplesdescribe how to prepare the various compounds and/or perform the variousprocesses of the invention and are to be construed as merelyillustrative, and not limitations of the preceding disclosure in any waywhatsoever. Those skilled in the art will promptly recognize appropriatevariations from the procedures both as to reactants and as to reactionconditions and techniques.

Preparation 1 1-[4-(Phenylsulfonyl)phenyl]hydrazine (V)

[0118]

[0119] A mixture of 4-chlorophenyl phenyl sulfone (10.1 g, 40.0 mmol),hydrazine mono-hydrate (30 mL), and triethylamine (4 drops) in ethyleneglycol (20 mL) is heated at 150° for 15 hr. Upon cooling, the mixture isdiluted with H₂O and filtered. The residual solid is washed with H₂Ountil the washings are neural (pH=6). This material is then trituratedwith methylene chloride and dried under reduced pressure at 50° to givethe title compound, IR (drift) 3282, 1586, 1514, 1306, 1291, 1158, 1145,1104, 996, 813, 756, 730, 717, 688 and 678 cm⁻¹; NMR (300 MHz, CDCl₃)7.70-7.85, 7.45-7.65, 6.79 and 4.22 δ; MS (EI) m/z 248 (M⁺), 125, 123,108, 107, 90, 80, 77, 63 and 51.

Preparation 2 1-[4-[(4-Fluorophenyl)sulfonyl]phenyl]hydrazine (V)

[0120]

[0121] Step I: 4-Fluorophenyl-4-nitrophenyl sulfide (III)

[0122] A mixture of 4-fluorothiophenol (I, 2.08 g, 19.5 mmol),1-chloro-4-nitrobenzene (II, 3.39 g, 21.5 mmol), and potassium carbonate(5.40 g, 39.0 mmol) in acetonitrile (75 mL) is stirred at 20-25° undernitrogen for 16 hr. The mixture is diluted with H₂O (100 mL) andextracted into methylene chloride (3×100 mL). The extracts are driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure to provide a quantitative yield of the desiredthioether, mp=84-90°; NMR (300 MHz, CDCl₃) 8.07, 7.45-7.60 and,7.05-7.25 δ.

[0123] Step II: 4-[(4-Fluorophenyl)sulfonyl]phenylamine (IV)

[0124] A hot mixture (100°) of 4-fluorophenyl 4-nitrophenyl sulfide(III, Step I, 1.91 g, 7.66 mmol) in glacial acetic acid (50 mL) istreated with hydrogen peroxide (30%, 2.60 mL), followed 20 min later bya second portion of hydrogen peroxide (30%, 1.70 mL). The mixturecontinued to heat for an additional 30 min, and is then allowed to coolto 20-25°. The mixture is concentrated to near dryness and filtered,rinsing the solid with H₂O. The solid is dried in a vacuum oven at 50°to give the intermediate sulfone, IR (drift) 1590, 1534, 1356, 1307,1294, 1242, 1166, 1156, 1109, 1101, 858, 839, 742, 687 and 665 cm⁻¹; NMR(300 MHz, CDCl₃) 8.35, 8.12, 7.95-8.05 and 7.15-7.30 δ; MS (EI) m/z 281(M⁺), 159, 143, 111, 95, 95, 83, 76, 74 and 51.

[0125] A mixture of 4-fluorophenyl 4-nitrophenyl sulfone (1.89 g, 6.72mmol) in methanol (80 ml) is treated with Rhodium on carbon (5%, 95 mg)and hydrogenated at 20 psi for 24 hr. The mixture is filtered, rinsingwith methylene chloride (2×100 mL) and methanol (100 mL). The filtrateis concentrated to near dryness and refiltered, rinsing with minimalmethanol. The solid is dried in the vacuum oven at 50° to give thedesired amine, mp=204-205°: IR(drift)3473, 3373, 1638, 1592, 1489, 1303,1294, 1285, 1231, 1159, 1144, 1107, 834, 713 and 689 cm⁻¹; NMR (300 MHz,CDCl3) 7.80-7.95, 7.60-7.75, 7.13, 6.60-6.75 and 4.17 δ; MS (EI) m/z 251(M⁺), 140, 108, 95, 92, 80, 65, 65, 63 and 51.

[0126] Step III: 1-[4-[(4-fluorophenyl)sulfonyl]phenyl]hydrazine (V)

[0127] A mixture of 4-[(4-fluorophenyl)sulfonyl]phenylamine (IV, StepII, 3.10 g, 12.3 mmol) in concentrated hydrochloric acid (30 mL) at 0°is treated with sodium nitrite (934 mg, 13.5 mmol) in H₂O (15 mL). After30 min, the mixture is treated with stannous chloride (5.57 g, 24.7mmol) in concentrated hydrochloric acid (15 mL). The mixture is stirredat 0° for 1 hr, and then at 20-25° for 1 hr. The precipitate iscollected and slurried in H₂O. The mixture is made basic (sodiumhydroxide, 50%) and the solid isolated. The material is partitionedbetween methylene chloride and saline. The organic layer is dried,filtered, and concentrated under reduced pressure to give the titlecompound, NMR (300 MHz, CDCl₃) 7.85-7.95, 7.74, 7.13, 6.85, 5.64 and3.65 δ.

Example 1 9-(Phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

[0128]

[0129] Step I: 1-Benzyl-4-azepanoneN-[4-(phenylsulfonyl)phenyl]hydrazone (VII)

[0130] A mixture of 1-[4-(phenylsulfonyl)phenyl]hydrazine (V,PREPARATION 1, 7.06 g, 28.4 mmol) and 4-benzylazapanone (VI, 5.78 g,28.4 mmol) in ethanol (130 mL) is treated with glacial acetic acid (8drops) and heated at reflux for 1 hr. Upon cooling, the precipitate iscollected, washed with ethanol and dried in the vacuum oven at 50° togive the desired compound, mp=142-146°. The filtrate is concentrated andpurified via flash chromatography (ethyl acetate/heptane; 65/35) toprovide additional product as two regioisomers. Analytical data for oneisomer: IR (drift) 1593, 1511, 1323, 1301, 1261, 1148, 1106, 1069, 833,758, 748, 735, 709, 689 and 600 cm⁻¹; NMR (300 MHz, CDCl₃) 7.85-7.95,7.77, 7.40-7.65, 7.15-7.35, 7.06, 3.65, 2.65-2.85, 2.55-2.65, 2.35-2.45and, 1.70-1.85; MS (EI) m/z 433 (M⁺), 186, 120, 108, 97, 96, 91, 82, 77,65 and 51. Analytical data for the slower eluting isomer: IR (drift)1593, 1509, 1324, 1296, 1285, 1264, 1148, 1106, 1085, 1069, 834, 735,710, 688 and 605 cm⁻¹; NMR (300 MHz, CDCl₃) 7.85-7.95, 7.70-7.85,7.35-7.55, 7.15-7.35, 7.06, 3.60, 2.55-2.75, 3.32-2.45 and 1.85-2.00; MS(EI) m/z 433 (M⁺), 187, 186, 120, 108, 97, 91, 82, 77, 65 and 51.

[0131] Step II:3-Benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(VIII)

[0132] A mixture of 1-benzyl-4-azepanoneN-[4-(phenylsulfonyl)phenyl]hydrazone (VII, Step I, 3.41 g, 7.86 mmol)and polyphosporic acid (4.78 g) in o-xylene (550 mL) is heated at 100°under nitrogen for 3 hr. Upon cooling, the xylene is decanted and theresidual material partitioned between methylene chloride/methanol andsodium hydroxide (0.5 M). The phases are separated and the aqueous layeris further extracted with more methylene chloride/methanol (2×). Theorganic phases are combined and dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure to give an oil. Theoil is purified by flash chromatography (Biotage 40M; ethylacetate/heptane, 7/3) to give the desired indole, mp=86-88°, dec; IR(drift) 3343, 2910, 1475, 1449, 1337, 1301, 1146, 1131, 1090, 748, 731,719, 698, 688 and 627 cm⁻¹; NMR (300 MHz, CDCl₃) 8.10-8.20, 8.06, 7.96,7.66, 7.25-7.55, 3.85 and 2.90-3.05 δ; MS (EI) m/z 416 (M⁺), 296, 154,146, 134, 134, 132, 120, 91 and 65.

[0133] Step III:9-(Phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (IX)

[0134] A mixture of3-benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(VIII, Step II, 453 mg, 1.09 mmol) in methanol (50 mL) is treated withpalladium hydroxide (118 mg) and hydrogenated at 30 psi for 5 days. Themixture is filtered, rinsing with methanol and methylene chloride, andthe filtrate concentrated under reduced pressure to give an amorphoussolid. The material is purified by flash chromatography (Biotage 40M;methanol/methylene chloride, 5/95; methanol/methylene chloride/ammoniumhydroxide, 20/79/1) to give the title compound. Analytical data for thehydrochloride salt, mp=290-291.5°; IR (drift) 3382, 2751, 2698, 2689,2646, 2438, 1297, 1150, 1131, 1095, 801, 759, 722, 684 and 616 cm⁻¹; NMR(300 MHz, DMSO-d₆) 11.65, 7.35, 8.05-8.15, 7.85-7.95, 7.40-7.65,3.20-3.40 and 3.10-3.25 8; MS (EI) m/z 326 (M⁺), 298, 297, 286, 285,284, 143 and 77; HRMS (FAB) calculated for C₁₈H₁₉N₂O₂S=327.1167, found327.1165.

Example 29-[(4-Fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

[0135]

[0136] Following the general procedure of EXAMPLE 1 (Steps I-III) andmaking non-critical variations,1-[4-[(4-fluorophenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2) isconverted to the title compound, mp=168°, dec.; IR (drift) 2923, 1590,1491, 1475, 1336, 1308, 1287, 1236, 1147, 1131, 1089, 837, 816, 749 and683 cm⁻¹; NMR (300 MHz, CDCl₃) 8.05-8.15, 8.05, 7.90-8.00, 7.55-7.65,7.30-7.35, 7.12, 3.05-3.15 and 2.90-3.00 δ; HRMS (FAB) calculated forC₁₈H₁₈FN₂O₂S=345.1073, found 345.1087.

Example 39-[(4-Methylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

[0137]

[0138] Following the general procedure of EXAMPLE 1 (Steps I-III) andmaking non-critical variations,1-[4-[(4-methylphenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2) isconverted to the title compound, mp=125°, dec; IR (drift) 3027, 2921,2830, 1475, 1453, 1336, 1298, 1287, 1150, 1130, 1090, 812, 747, 682 and658 cm⁻¹; NMR (300 MHz, CDCl₃) 8.12, 7.83, 7.55-7.65, 7.20-7.35,3.05-3.20, 2.90-3.05 and 2.36 δ; MS (EI) m/z 340 (M⁺), 311, 298, 154,144, 143, 115, 91, 91 and 65; HRMS (FAB) calculated forC₁₉H₂₁N₂O₂S=341.1324, found 341.1311.

Example 49-[(4-Methoxyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

[0139]

[0140] Following the general procedure of EXAMPLE 1, and makingnon-critical variations, 1-[4-[(4-methylphenyl)sulfonyl]phenyl]hydrazine(V, PREPARATION 2) is converted to the title compound, mp=139°, dec.; IR(drift) 2927, 2837, 1593, 1496, 1335, 1312, 1293, 1260, 1142, 1130,1092, 834, 802, 748 and 683 cm⁻¹; NMR (300 MHz, DMSO-d₆) 11.30,7.90-8.00, 7.75-7.85, 7.40-7.50, 7.30-7.40, 7.00-7.10, 3.77 and2.75-3.05; MS (EI) m/z 356 (M⁺), 327, 314, 155, 154, 143, 143, 115, 77and 57; HRMS (FAB) calculated for C₁₉H₂₁N₂O₃S=357.1273, found 357.1275.

Example 59-[(3-Fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

[0141]

[0142] Following the general procedure of EXAMPLE 1, and makingnon-critical variations, 1-[4-[(3-fluorophenyl)sulfonyl]phenyl]hydrazine(V, PREPARATION 2) is converted to the title compound, mp=153-156°: IR(drift) 2926, 2867, 2855, 1474, 1311, 1296, 1225, 1151, 1129, 1082, 773,742, 698, 677 and 629 cm⁻¹; NMR (300 MHz, DMSO-d₆) 11.37, 8.00-8.10,7.70-7.80, 7.30-7.75 and 2.75-2.95 δ; MS (EI) m/z 344 (M⁺), 315, 302,154, 144, 143, 128, 128, 115 and 73; HRMS (FAB) calculated forC₁₈H₁₈FN₂O₂S=345.1073, found 345.1075.

Example 69-[(3-Methoxylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

[0143]

[0144] Following the general procedure of EXAMPLE 1, and makingnon-critical variations,1-[4-[(3-methoxyphenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2) isconverted to the title compound, mp=232-235°, dec.; IR (drift) 2976,2963, 2832, 2805, 2770, 2739, 1475, 1303, 1248, 1151, 1141, 746, 694,682 and 629 cm⁻¹; NMR (300 MHz, DMSO-d₆) 11.63, 9.31, 8.10-8.15,7.35-7.60, 7.10-7.20, 3.79, 3.20-3.40 and 3.05-3.40 δ; MS (EI) m/z 356(M⁺), 327, 314, 107, 74, 73, 59, 57, 57 and 56; MS (FAB) m/z 357 (MH⁺),356, 328, 177, 155, 121, 103, 89; HRMS (FAB) calculated forC₁₉H₂₁N₂O₃S=357.1273, found 357.1277.

Example 79-[(4-Trifluoromethyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

[0145]

[0146] Following the general procedure of EXAMPLE 1, and makingnon-critical variations,1-[4-[(4-trifluoromethylphenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION2) is converted to the title compound, mp=278-279°, dec.; IR (drift)2773, 2756, 2732, 1321, 1306, 1178, 1156, 1133, 1122, 1108, 1061, 844,716, 623 and 618 cm⁻¹; NMR (300 MHz, DMSO-d₆) 8.05-8.20, 7.90-8.00,7.55-7.45, 7.45-7.55 and 3.05-3.40 δ; MS (EI) m/z 394 (M⁺), 365, 352,154, 143, 73, 71, 59, 58 and 57.

Example 86-Ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

[0147]

[0148] Step I:3-Benzyl-6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0149] A 0° mixture of 3-benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino [4,5-b]indole (EXAMPLE 1, Step II, 301 mg, 0.723mmol) in dry DMF (5 mL) is treated with sodium hydride (60% in oil, 32mg, 0.795 mmol), and allowed to warm to 20-25° over 1.5 hr. The mixtureis then cooled (0°), treated with iodoethane (64 μL, 0.795 mmol) andallowed to slowly warm to 20-25° under nitrogen over 72 hr. Theresultant mixture is diluted with ethyl acetate (50 mL) and washed withH₂O (3×25 mL) and saline (25 mL). The organic layer is dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure to give a solid. The solid is purified via chromatography (20 gSG; ethyl acetate/heptane, 65/35) to give the indole as a solid,mp=188-191°; IR (drift) 1477, 1373, 1300, 1289, 1157, 1148, 1094, 766,756, 738, 728, 701, 694, 645 and 621 cm⁻¹; NMR (300 MHz, CDCl₃)8.10-8.20, 7.90-8.05, 7.65-7.75, 7.20-7.50, 4.11, 3.82, 2.85-3.05 and1.27 δ; MS (EI) m/z 444 (M⁺), 326, 324, 312, 167, 154, 132, 118, 96, 91and 64.

[0150] Step II: 6-Ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (X)

[0151] A mixture of3-benzyl-6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Step I, 107 mg, 0.241 mmol) in methanol (20 mL, 1 drop concentratedhydrochloric acid) is treated with palladium on carbon (10%, 32 mg) andhydrogenated at 25 psi for 48 hr. The resulting mixture is filtered,rinsing with methanol and methylene chloride, and the filtrate isconcentrated to a solid. The solid is purified via chromatography (10 gSG; methanol/methylene chloride/ammonium hydroxide, 20/79/1) to give thetitle compound, mp=224°, dec.; IR (drift) 2982, 2935, 2743, 1473, 1449,1312, 1300, 1151, 1091, 819, 768, 728, 691, 647 and 623 cm⁻¹; NMR (300MHz, DMSO-d₆) 8.09, 7.85-7.95, 7.45-7.65, 4.20, 2.95-3.25 and 1.15 δ; MS(EI) m/z 354 (M⁺), 312, 170, 167, 153, 143, 114, 78, 76 and 51; HRMS(FAB) calculated for C₂₀H₂₃N₂O₂S=355.1480, found 355.1488.

Example 96-Ethyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

[0152]

[0153] Following the general procedure of EXAMPLE 8, and makingnon-critical variations,3-benzyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 2) is converted to the title compound, mp=227-233°, dec.; IR(drift) 2972, 2834, 2755, 2713, 2679, 1589, 1490, 1471, 1312, 1293,1223, 1148, 1094, 715 and 693 cm⁻¹; MS (EI) m/z 372 (M⁺), 331, 330, 171,171, 154, 143, 143, 91 and 57; NMR (300 MHz, DMSO-d₆) 9.30, 8.18, 8.02,7.55-7.70, 7.41, 4.24, 3.10-3.40 and 1.19 δ; MS (FAB) m/z 373 (MH⁺),372, 371, 344 and 330; HRMS (FAB) calculated for C₂₀H₂₂FN₂O₂S=373.1386,found 373.1371.

Example 106-Methyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

[0154] Following the general procedure of EXAMPLE 8, and makingnon-critical variations,3-benzyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 2) is converted to the title compound, mp>300°; IR (drift)2775, 1589, 1489, 1310, 1288, 1237, 1149, 1091, 841, 836, 805, 718, 667,639 and 605 cm⁻¹; NMR (300 MHz, DMSO-d₆) 9.51, 8.17, 8.01, 7.63, 7.41,3.72 and 3.10-3.45 δ.

Example 116-Methyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

[0155]

[0156] Following the general procedure of EXAMPLE 8, and makingnon-critical variations,3-benzyl-9-[(4-trifluoromethyl)phenyl]sulfonyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 7) is converted to the title compound, mp=286°, dec.; IR(drift) 2740, 2716, 1321, 1309, 1187, 1172, 1155, 1132, 1109, 1098,1063, 845, 719, 648 and 625 cm⁻¹; NMR (300 MHz, DMSO-d₆) 9.31, 8.19,8.13, 7.93, 7.64, 3.71 and 3.10-3.40 δ.

Example 126-Ethyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

[0157]

[0158] Following the general procedure of EXAMPLE 8, and makingnon-critical variations,3-benzyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 7) is converted to the title compound, mp=170-179°, dec.; IR(drift) 2762, 1326, 1302, 1294, 1190, 1184, 1171, 1153, 1138, 1109,1095, 1064, 830, 716 and 618 cm⁻¹; NMR (300 MHz, DMSO-d₆) 9.40, 8.20,8.14, 7.93, 7.65, 4.15-4.30, 3.10-3.45 and 1.10-1.20 δ.

Example 136-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

[0159]

[0160] Step I: 1-Benzoyl-4-azepanoneN-[4-(phenylsulfonyl)phenyl]hydrazone

[0161] A mixture of 1-[4-(phenylsulfonyl)phenyl]hydrazine (2.05 g, 8.26mmol) and 4-benzoylazapanone (1.97 g, 9.09 mmol) in ethanol (40 mL) istreated with glacial acetic acid (8 drops) and heated at reflux for 1hr. Upon cooling, the precipitate is collected, washed with ethanol anddried in the vacuum oven (50°) to give the desired hydrazone,mp=202-204°.

[0162] Step II:3-Benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0163] A mixture of 1-benzoyl-4-azepanoneN-[4-(phenylsulfonyl)phenyl]hydrazone (Step I, 2.00 g, 4.47 mmol) indichloroethane/phosphoric acid 84% (1/1, 40 mL) is heated at reflux for16 hr. Upon cooling, the product is diluted with saline and extractedinto methylene chloride (3×). The extracts are dried, filtered, andconcentrated under reduced pressure to give a solid. The solid ispurified via silica gel chromatography (Biotage 40M; ethylacetate/heptane, 75/25) to give the desired indole.

[0164] Step III:3-Benzoyl-6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0165] A 0° mixture of3-benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Step II, 1.61 g, 3.74 mmol) in dry DMF (18 mL) is treated with sodiumhydride (60% in oil, 165 mg, 4.11 mmol). After 30 min, the mixture istreated with iodomethane (256 μL, 4.11 mmol) and allowed to slowly warmto 20-25° under nitrogen over 16 hr. The resultant mixture is dilutedwith H₂O and filtered. The residual solid is triturated with refluxingmethanol, isolated, and dried in the vacuum oven at 50° to give thedesired indole, mp=254-255°.

[0166] Step IV:6-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0167] A mixture of3-benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Step III, 1.25 g, 2.81 mmol) and potassium hydroxide (1.58 g, 28.1mmol) in ethylene glycol (30 mL) is heated at 130° under nitrogen for 92hr. Upon cooling, the mixture is diluted with H₂O and extracted intoethyl acetate (3×). The combined extracts are washed with H₂O (2×) andsaline, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure to give a solid. The solid isdissolved in hot methylene chloride/methanol and treated with methanolichydrochloric acid. The resultant mixture is concentrated andcrystallized from ethyl acetate/methanol to give the title compound,mp>300°; IR (drift) 2820, 2792, 2747, 2717, 2704, 2665, 2651, 1299,1147, 1096, 803, 729, 687, 643 and 621 cm⁻¹; NMR (300 MHz, DMSO-d₆)9.41, 8.13, 7.85-7.95, 7.50-7.65, 3.70 and 3.10-3.40 δ; MS (EI) m/z 340(M⁺), 298, 157, 156, 128, 78, 74, 73, 58 and 57; HRMS (FAB) calculatedfor C₁₉H₂₁N₂O₂S=341.1324, found=341.1319.

Example 149-[(3,4-Difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

[0168]

[0169] Following the general procedure of EXAMPLE 1 (steps I-III) andmaking non-critical variations,1-[4-[(3,4-difluorophenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2)is converted to the title compound, mp=320°, dec; IR (drift) 2732, 1507,1310, 1293, 1277, 1147, 1128, 1116, 1072, 800, 751, 686, 627, 622 and610 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ11.75, 9.50, 8.10-8.20, 7.75-7.85,7.55-7.70, 7.40-7.50, 3.25-3.40 and 3.10-3.25; OAMS (supporting ionsat): ESI+363.1, ESI−361.0.

Example 159-[(3,5-Difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

[0170]

[0171] Following the general procedure of EXAMPLE 1 (steps I-III) andmaking non-critical variations,1-[4-[(3,5-difluorophenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2)is converted to the title compound, mp=313-315°, dec; IR (drift) 3256,1606, 1591, 1307, 1285, 1269, 1153, 1138, 1122, 983, 850, 795, 678, 666and 618 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ11.70, 9.35, 8.15-8.25, 7.40-7.85and 3.10-3.40; MS (EI) m/z 362 (M⁺), 333, 320, 154, 142, 127, 115, 113,92 and 63.

Example 169-[(3,5-Difluorophenyl)sulfonyl]-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

[0172]

[0173] Following the general procedure of EXAMPLE 13 (steps I-IV) andmaking non-critical variations,1-[4-[(3,5-difluorophenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2)(EXAMPLE 2) is converted to the title compound, mp=337-340°, dec; IR(drift) 2767, 2750, 1603, 1437, 1308, 1295, 1144, 1129, 988, 807, 709,681, 675, 650 and 627 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ9.35, 8.20-8.30,7.60-7.80, 3.71 and 3.15-3.45; MS (EI) m/z 376 (M⁺), 334, 334, 156, 114,113, 64, 63, 57, 52 and 51; HRMS (FAB) calculated forC₁₉H₁₉F₂N₂O₂S=377.1135, found=377.1125.

Example 179-[(4-(2-Hydroxyethoxy)phenyl)sulfonyl]-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

[0174]

[0175] Following the general procedure of EXAMPLE 13 (steps I-IV) andmaking non-critical variations,1-[4-[(4-fluorophenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2) isconverted to the title compound, mp=285-287°, dec; IR (drift) 2957,2835, 2811, 2760, 1592, 1492, 1458, 1309, 1293, 1261, 1142, 1092, 721,637 and 618 cm⁻¹; NMR (300MHz, DMSO-d₆) δ9.43, 8.09, 7.81, 7.57, 7.06,4.85-4.95, 3.95-4.05, 3.69 and 3.00-3.45; MS (EI) m/z 400 (M⁺), 86, 84,77, 73, 72, 71, 58, 57, 56 and 51; HRMS (FAB) calculated forC₂₁H₂₅N₂O₄S=401.1535, found=401.1540.

Example 183,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(X)

[0176]

[0177] A mixture of6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 13, 341 mg, 1.00 mmol) in acetonitrile (5 mL) is treated withformaldehyde (37%, 0.400 mL, 5.00 mmol), sodium cyanoborohydride (101mg, 1.60 mmol) and glacial acetic acid (1 drop). After 5 hr, the mixtureis diluted with ethyl acetate and then washed with water and saline. Theorganic layer is dried, filtered, and concentrated. The concentrate isdissolved in methylene chloride/methanol and treated with methanolichydrochloric acid. The solvent is then removed and the residual solidcrystallized from hot ethyl acetate/methanol to give the title compound,mp=283-286°; IR (drift) 2523, 2477, 2453, 2428, 1479, 1311, 1304, 1283,1150, 1094, 756, 730, 694, 644 and 623 cm⁻¹; NMR (300 MHz, DMSO-d₆)δ11.00, 8.16, 7.85-7.95, 7.50-7.65, 3.70, 3.15-3.45 and 2.89; MS (FAB)m/z 355 (MH⁺), 354, 353, 58 and 44; HRMS (FAB) calculated forC₂₀H₂₃N₂O₂S=355.1480, found=355.1488.

Example 193-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(X)

[0178]

[0179] Following the general procedure of EXAMPLE 18, and makingnon-critical variations,9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (EXAMPLE 1)is converted to the title compound, mp=150°, dec; IR (drift) 2623, 1474,1447, 1338, 1301, 1173, 1152, 1129, 1090, 755, 741, 719, 689, 673 and615 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ11.68, 8.14, 7.85-7.95, 7.40-7.65,3.10-3.45 and 2.88; MS (EI) m/z 340 (M⁺), 296, 77, 74, 73, 72, 71, 58,57, 56 and 51; HRMS (FAB) calculated for C₁₉H₂₁N₂O₂S=341.1324,found=341.1331.

Example 209-[(4-fluorophenyl)sulfonyl]-3-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(X)

[0180]

[0181] Following the general procedure of EXAMPLE 18, and makingnon-critical variations,6-methyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 10) ) is converted to the title compound, mp=282-283°, dec; IR(drift) 2479, 2437, 1589, 1490, 1310, 1284, 1239, 1161, 1144, 1092, 838,809, 718, 677 and 667 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ10.60, 8.17, 7.99,7.62, 7.39, 3.71, 3.10-3.75 and 1.31; MS (EI) m/z 400 (M⁺), 385, 328,315, 169, 167, 127, 85, 71, 70 and 56; HRMS (FAB) calculated forC₂₂H₂₆FN₂O₂S=401.1699, found=401.1709.

Examples 21-44

[0182] Following the general procedure of the above EXAMPLEs, makingnon-critical variations and starting with the corresponding appropriatestarting materials, the following compounds are obtained:

[0183] 21.1-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0184] 22.2-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0185] 23.4-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0186] 24.5-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0187] 25.9-[(4-Fluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0188] 26.9-[(4-Fluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0189] 27.9-[(4-Fluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0190] 28.9-[(4-Fluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0191] 29.1,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0192] 30.2,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0193] 31.4,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0194] 32.5,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0195] 33.9-[(4-Fluorophenyl)sulfonyl]-1,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0196] 34.9-[(4-Fluorophenyl)sulfonyl]-2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0197] 35.9-[(4-Fluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0198] 36.9-[(4-Fluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0199] 37.9-[(3,5-Difluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0200] 38.9-[(3,5-Difluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0201] 39.9-[(3,5-Difluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0202] 40.9-[(3,5-Difluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0203] 41.9-[(3,5-Difluorophenyl)sulfonyl]-1,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0204] 42.9-[(3,5-Difluorophenyl)sulfonyl]-2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0205] 43.9-[(3,5-Difluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0206] 44.9-[(3,5-Difluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

1. A 9-arylsulfone of the formula (XII)

where R₃ is: (1) —H, (2) C₁-C₄ alkyl, (3) C₀-C₄-φ where the -φsubstituent is optionally substituted with 1 or 2 (a) —F, —Cl, —Br, —I,(b) —O—R₃₋₁ where R₃₋₁ is: —H, C₁-C₄ alkyl, -φ, (c) —CF₃, (d)—CO—NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃ are —H and C₁-C₄ alkyl, and where R₃₋₂and R₃₋₃ are taken with the attached nitrogen atom to form a ringselected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl and1-morpholinyl, (e) —NH—SO₂—R₃₋₄ where R₃₋₄ is —H and C₁-C₄ alkyl, (f)—NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃ are as defined above, (g) —NR₃₋₄—CO—R₃₋₄where R₃₋₄ is as defined above, (h) —SO₂—NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃are as defined above, (I) —C═N, (j) —NO₂, where R_(N) is: (1) —H, (2)C₁-C₄ alkyl, (3) C₀-C₄-φ where the -φ substituent is optionallysubstituted with 1 or 2 (a) —F, —Cl, —Br, —I, (b) —O—R_(N-1) whereR_(N-1) is —H, C₁-C₄ alkyl, -φ, (c) —CF₃, (d) —CO—NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) are —H and C₁-C₄ alkyl, and where R₃₋₂ and R₃₋₃ aretaken with the attached nitrogen atom to form a ring selected from thegroup consisting of 1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl, (e)—NH—SO₂—R_(N-4) where R_(N-4) is —H and C₁-C₄ alkyl, (f)—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined above, (g)—NR_(N-4)—CO—R_(N-4) where R_(N-4) is as defined above, (h)—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined above, (I)—C≡N, (j) —NO₂, where R_(X) is: (1) —H (2) —F, —Cl, —Br, —I, (3)—O—R_(X-1) where R_(X-1) is: —H, C₁-C₄ alkyl, -φ, (4) —CF₃, (5)—CO—NR_(X-2)R_(X-3) where R_(X-2) and R_(X-3) are as defined above, (6)—NH—SO₂—R_(X-4) where R_(X-4) is as defined above, (7) —NR_(X-2)R_(X-3)where R_(X-2) and R_(X-3) are as defined above, (8) —NR_(X-4)—CO—R_(X-4)where R_(X-4) is as defined above, (9) —SO₂—NR_(X-2)R_(X-3) whereR_(X-2) and R_(X-3) are as defined above, (10) —C≡N, (11) —NO₂; where R₉is: (1) —H, (2) —F, —Cl, (3) C₁-C₄ alkyl, (4) C₁-C₃ alkoxy, (5) —CF₃,(6) C₀-C₄-φ where the -φ substituent is optionally substituted with 1 or2 (a) —F, —Cl, —Br, —I, (b) —O—R₉₋₁ where R₉₋₁ is: —H, C₁-C₄ alkyl, -φ,(c) —CF₃, (d) —CO—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are —H and C₁-C₄ alkyl,and where R₉₋₂ and R₉₋₃ are taken with the attached nitrogen atom toform a ring selected from the group consisting of 1-pyrrolidinyl,1-piperazinyl and 1-morpholinyl, (e) —NH—SO₂—R₉₋₄ where R₉₋₄ is —H andC₁-C₄ alkyl, (f) —NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above,(g) —NR₉₋₄—CO—R₉₋₄ where R₉₋₄ is as defined above, (h) —SO₂—NR₉₋₂R₉₋₃where R₉₋₂ and R₉₋₃ are as defined above, (I) —C≡N, (j) —NO₂ (7) —OR₉₋₁where R₉₋₁ is as defined above, (8) —CO—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃are as defined above, (9) —NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as definedabove, (10) —NH—SO₂—R₉₋₄ where R₉₋₄ is as defined above, (11)—NH—CO₂—R₉₋₂ where R₉₋₂ is as defined above and pharmaceuticallyacceptable salts thereof.
 2. A 9-arylsulfone (XII) according to claim 1where R₃ is selected from the group consisting of —H and C₁-C₂ alkyl. 3.9-arylsulfone (XII) according to claim 2 where R₃ is —H.
 4. A9-arylsulfone (XII) according to claim 1 where R_(N) is selected fromthe group consisting of —H and C₁-C₄ alkyl.
 5. A 9-arylsulfone (XII)according to claim 4 where R_(N) is —H, C₁ alkyl and C₂ alkyl.
 6. A9-arylsulfone (XII) according to claim 1 where R_(X) is selected fromthe group consisting of —H, —F and —Cl.
 7. A 9-arylsulfone (XII)according to claim 6 where R_(X) is —H.
 8. A 9-arylsulfone (XII)according to claim 1 where R₉ is selected from the group consisting of—H, —F, —Cl, C₁-C₃ alkyl, C₁-C₃ alkoxy and —CF₃.
 9. A 9-arylsulfone(XII) according to claim 8 where R₉ is —H, —F, —Cl, C₁ alkyl, C₁ alkoxy,and —CF₃.
 10. A 9-arylsulfone (XII) according to claim 8 where the R₉substituent is in the 3- or 4-position.
 11. A 9-atylsulfone (XII)according to claim 1 where the pharmaceutically acceptable salt isselected from the group consisting of salts of methanesulfonic,hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic,citric, tartaric, fumaric, maleic, CH₃—(CH₂)_(n)—COOH where n is 0 thru4, HOOC—(CH₂)_(n)—COOH where n is as defined above.
 12. A 9-arylsulfone(XII) according to claim 11 where the pharmaceutically acceptable saltis selected from the group consisting of salts of hydrochloric, maleateand methanesulfonic acids.
 13. A 9-arylsulfone (XII) according to claim12 where the pharmaceutically acceptable salt is the salt ofhydrochloric acid.
 14. A 9-arylsulfone (XII) according to claim 1 wherethe substituted 9-arylsulfone is selected from the group consisting of:9-(phenylsulfonyl)-1,2,3,4,5 ,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-methylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-methoxyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, 9-[(3-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3-methoxylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-trifluoromethyphenyl)sulfonyl]1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,6-ethyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,6-methyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,6-methyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,6-ethyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleand6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.15. A 9-arylsulfone (XII) according to claim 14 where the substituted9-arylsulfone is6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.16. A 9-arylsulfone (XII) according to claim 1 where the substituted9-arylsulfone is selected from the group consisting of:9-[(3,4-difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-6methyl1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-(2-hydroxyethoxy)phenyl)sulfonyl]-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,3,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,3-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleand9-[(4-fluorophenyl)sulfonyl]-3-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.17. A 9-arylsulfone (XII) according to claim 1 where the substituted9-arylsulfone is selected from the group consisting of:1-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,2-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,4-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,5-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,1,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,2,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,4,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,5,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-1,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-1,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.18. A thio ether of formula (III)

where R₉ and R_(X) are as defined in claim
 1. 19. A thio ether accordingto claim 18 where R₉ is selected from the group consisting of —H, —F,—Cl, C₁-C₃ alkyl, C₁-C₃ alkoxy and —CF₃ and where R_(X) is selected fromthe group consisting of —H, —F and —Cl.
 20. An amine of formula (IV)

where R₉ and R_(X) are as defined in claim
 1. 21. An amine according toclaim 20 where R₉ and R_(X) are as defined in claim
 19. 22. A hydrazineof formula (V)

where R₉ and R_(X) are as defined in claim
 1. 23. A hydrazine accordingto claim 22 where R₉ and R_(X) are as defined in claim
 19. 24. Acompound of formula (VII)

where PG is selected from the group consisting of φ—CH₂—, φ—CO—,φ—CH₂—CO₂— and —CO—O—C(CH₃)₃ where R₉ and R_(X) are as defined inclaim
 1. 25. A compound according to claim 24 where PG is φ—CH₂— orφ—CO— and where R₉ and R_(X) are as defined in claim
 19. 26. A protected9-arylsulfone of formula (VII)

where PG is as defined in claim 24 and R₉ and R_(X) are as defined inclaim
 1. 27. A protected 9-arylsulfone according to claim 26 where PG isas defined in claim 25 and where R₉ and R_(X) are as defined in claim19.
 28. A method of treating a human who has a condition selected fromthe group consisting of anxiety, depression, schizophrenia, stressrelated disease, panic, a phobia, obsessive compulsive disorder,obeisity, post-traumatic stress syndrome who is in need of suchtreatment which comprises administering an effective amount of a9-arylsulfone of the formula (XII)

where R₃ is: (1) —H, (2) C₁-C₄ alkyl, (3) C₀-C₄-φ where the -φsubstituent is optionally substituted with 1 or 2 (a) —F, —Cl, —Br, —I,(b) —O—R₃₋₁ where R₃₋₁ is: —H, C₁-C₄ alkyl, -φ, (c) —CF₃, (d)—CO—NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃ are —H and C₁-C₄ alkyl, and where R₃₋₂and R₃₋₃ are taken with the attached nitrogen atom to form a ringselected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl and1-morpholinyl, (e) —NH—SO₂—R₃₋₄ where R₃₋₄ is —H and C₁-C₄ alkyl, (f)—NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃ are as defined above, (g) —NR₃₋₄—CO—R₃₋₄where R₃₋₄ is as defined above, (h) —SO₂—NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃are as defined above, (I) —C≡N, (j) —NO₂, where R_(N) is: (1) —H, (2)C₁-C₄ alkyl, (3) C₀C₄-φ where the -φ substituent is optionallysubstituted with 1 or 2 (a) —F, —Cl, —Br, —I, (b) —O—R_(N-1) whereR_(N-1) is —H, C₁-C₄ alkyl, -φ, (c) —CF₃, (d) —CO—NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) are —H and C_(l)-C₄ alkyl, and where R₃₋₂ and R₃₋₃are taken with the attached nitrogen atom to form a ring selected fromthe group consisting of 1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl,(e) —NH—SO₂—R_(N-4) where R_(N-4) is —H and C₁-C₄ alkyl, (f)—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined above, (g)—NR_(N-4)—CO—R_(N-4) where R_(N-4) is as defined above, (h)—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined above, (I)—C≡N, (j) —NO₂, where R_(X) is: (1) —H (2) —F, —Cl, —Br, —I, (3)—O—R_(X-1) where R_(X-1) is: —H, C₁-C₄ alkyl, -φ, (4) —CF₃, (5)—CO—NR_(X-2)R_(X-3) where R_(X-2) and R_(X-3) are as defined above, (6)—NH—SO₂—R_(X-4) where R_(X-4) is as defined above, (7) —NR_(X-2)R_(X-3)where R_(X-2) and R_(X-3) are as defined above, (8) —NR_(X-4)—CO—R_(X-4)where R_(X-4) is as defined above, (9) —SO₂—NR_(X-2)R_(X-3) whereR_(X-2) and R_(X-3) are as defined above, (10) —C≡N, (11) —NO₂; where R₉is: (1) —H, (2) —F, —Cl, (3) C₁-C₄ alkyl, (4) C₁-C₃ alkoxy, (5) —CF₃,(6) C₀C₄-φ where the -φ substituent is optionally substituted with 1 or2 (a) —F, —Cl, —Br, —I, (b) —O—R₉₋₁ where R₉₋₁ is: —H, C₁-C₄ alkyl, -φ,(c) —CF₃, (d) —CO—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are —H and C₁-C₄ alkyl,and where R₉₋₂ and R₉₋₃ are taken with the attached nitrogen atom toform a ring selected from the group consisting of 1-pyrrolidinyl,1-piperazinyl and 1-morpholinyl, (e) —NH—SO₂—R₉₋₄ where R₉₋₄ is —H andC₁-C₄ alkyl, (f) —NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above,(g) —NR₉₋₄—CO—R₉₋₄ where R₉₋₄ is as defined above, (h) —SO₂—NR₉₋₂R₉₋₃where R₉₋₂ and R₉₋₃ are as defined above, (I) —C≡N, (j) —NO₂ (7) —OR₉₋₁where R₉₋₁ is as defined above, (8) —CO—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃are as defined above, (9) —NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as definedabove, (10) —NH-SO₂—R₉₋₄ where R₉₋₄ is as defined above, (11)—NH—CO₂—R₉₋₂ where R₉₋₂ is as defined above, and pharmaceuticallyacceptable salts thereof.
 29. A method of treating a human according toclaim 28 where the condition is anxiety or depression.
 30. A method oftreating a human according to claim 28 where the administered is orally,sublingually, transdermally and parenterally.
 31. A method of treating ahuman according to claim 30 where the administration is oral.
 32. Amethod of treating a human according to claim 28 where theadministration is in divided doses either two, three or four timesdaily.
 33. A method of treating a human according to claim 28 where theeffective amount is from about 0.1 to about 50 mg/kg/day.
 34. A methodof treating a human according to claim 33 where the effective amount isfrom about 0.1 to about 10 mg/kg/day.
 35. A method of treating a humanaccording to claim 28 where the 9-arylsulfone of the formula (XII) isselected from the group consisting of9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-methylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-methoxyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3-methoxylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-trifluoromethyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,6-ethyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,6-methyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,6-methyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,6-ethyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,4-difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-(2-hydroxyethoxy)phenyl)sulfonyl]-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,3,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,3-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleand9-[(4-fluorophenyl)sulfonyl]-3-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.36. A method of treating a human according to claim 35 where the9-arylsulfone of the formula (XII) is6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.37. A method of treating a human according to claim 28 where the9-arylsulfone of the formula (XII) is selected from the group consistingof1-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,2-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,4-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,5-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,1,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,2,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,4,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,5,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-1,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(4-fluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-1,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,9-[(3,5-difluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.